[unreadable] The current application represents the Phase I component of a Fast-Track SBIR Grant by Inotek Corporation, proposing to conduct proof-of-concept efficacy testing with a novel, long-acting, regionally selective NO donor compound. There is a marked impairment of nitric oxide production in diabetic blood vessels, which importantly contributes to the pathogenesis of many diabetic complications, including foot ulcerations. The main hypothesis of the current study is that NO supplementation to the diabetic skin substitutes for the lacking NO, and restores vascular homeostasis. This approach is expected to provide short-term relief (against skin dryness, for example), as well as prevention of some of the long-term problems (such as foot ulcerations). As preliminary data we present evidence that NO production and cutaneous vasodilatation is impaired in diabetic patients. We also demonstrate that increased oxidative stress and downstream processes induced by the oxidants contribute to the pathogenesis of diabetic endothelial dysfunction. We also present evidence that DSI, a novel, long-acting nitric oxide donor provides selective vasodilatory effects in two non-dermal vascular beds (pulmonary and vaginal circulation). The central aim of our Phase I component is to perform proof-of-concept in vivo studies in control animals and in diabetic rodents, in order to demonstrate that our novel, dermally permeable NO donor formulation exerts significant vasodilatory effects. If these studies confirm that Inotek's NO donor formulation is an effective, prolonged and selective vasodilator in (both in control animals and in streptozotocin and NOD models of diabetes), a subsequent Phase II component will be triggered, which will focus on formal preclinical safety testing. In the Phase II component of the current SBIR application, we will propose to perform pre-clinical safety studies with GLP quality material. A GMP quality synthesis of the compound will be developed and the compound formulated as a topical cream. In addition, we propose formal safety studies and, for the final year of the project a clinical Phase I/II trial in healthy volunteers and in diabetic patients. Taken together, we request funds from the NIH to develop a potent, regionally selective NO donor, which is expected to be effective in reducing the incidence of some of the cardiovascular complications of established Type I and Type II diabetes. [unreadable] [unreadable]